Abstract
Although the effect of intensive systolic blood pressure lowering is widely recognized, treatment‐related low diastolic blood pressure still worrisome. This was a prospective cohort study based on the National Health and Nutrition Examination Survey. Adults (≥20 years old) with guideline‐recommended blood pressure were included and pregnant women were excluded. Survey‐weighted logistic regression and cox models were used for analysis. A total of 25 858 participants were included in this study. After weighted, the overall mean age of the participants was 43.17 (16.03) years, including 53.7% women and 68.1% non‐Hispanic white. Numerous factors were associated with low DBP (<60 mmHg), including advanced age, heart failure, myocardial infarction, and diabetes. The use of antihypertensive drugs was also associated with lower DBP (OR, 1.52; 95% CI, 1.26–1.83). DBP of less than 60 mmHg were associated with a higher risk of all‐cause death (HR, 1.30; 95% CI, 1.12–1.51) and cardiovascular death (HR, 1.34; 95% CI, 1.00–1.79) compared to those with DBP between 70 and 80 mmHg. After regrouping, DBP <60 mmHg (no antihypertensive drugs) was associated with a higher risk of all‐cause death (HR, 1.46; 95% CI, 1.21–1.75). DBP <60 mmHg after taking antihypertensive drugs was not associated with a higher risk of all‐cause death (HR, 0.99; 95% CI, 0.73–1.36). Antihypertensive drug is an important factor contributing to DBP below 60 mmHg. But the pre‐existing risk does not increase further with an additional reduction of DBP after antihypertensive drugs treatment.
Keywords: diastolic blood pressure, individual antihypertensive therapy, intensive blood pressure reduction, systolic blood pressure
1. INTRODUCTION
Although the global age‐standardized prevalence of hypertension has remained stable, absolute numbers have doubled since 30 years ago as the population grows and ages. 1 Hypertension is known as a significant risk factor for cardiovascular disease, chronic kidney disease, and all‐cause mortality. 2 , 3 , 4 Because blood pressure is a manageable risk factor, researchers never stop looking for the optimal blood pressure range. 5 The Framingham Heart Study and others have led the public to shift the focus of blood pressure management from diastolic to systolic blood pressure. 6 The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive systolic blood pressure (SBP) reduction (<120 mmHg vs. <140 mmHg) improved cardiovascular disease outcomes and all‐cause mortality in adults at high risk of cardiovascular disease. 7 This benefit of intensive blood pressure reduction has also been demonstrated in the elderly population. 8 Driven by the SPRINT trial, the American Heart Association Hypertension Guidelines recommend an intensive blood pressure target of less than 130/80 mmHg, nonetheless, the guidelines do not specify a lower limit for diastolic blood pressure (DBP). 9 Although the role of intensive blood pressure reduction has been widely recognized, the optimal range of DBP after SBP reduction by intensification has not been determined, and its impact on prognosis is still controversial. Previous studies have suggested that lower DBP may increase the risk of certain cardiovascular disease outcomes, resulting in a j‐shaped curve in the relationship between blood pressure and health risk. 10 , 11 More importantly, low DBP is often associated with enhanced blood pressure control and may compromise the efficacy of intensive blood pressure reduction. 12 , 13 The dilemma of whether to treat patients with isolated systolic hypertension with low DBP (<70 mmHg) cannot be ignored. 14 However, a recent Mendelian randomization study suggested that the association between low DBP and poor outcome is less likely to be attributed to its own effect on low DBP, and more likely to explain unmeasured confounders. 15 Risk factors related to low DBP and the relationship between low DBP and poor prognosis remain unclear, especially when SBP has reached the guideline‐recommended 130 mmHg.
Therefore, our study aims to explore the characteristics of the low DBP population and further investigate the association of DBP with death when SBP below 130 mmHg.
2. METHODS
2.1. Study design
We conducted a prospective cohort study utilizing data from the National Health and Nutrition Examination Survey (NHANES). The NHANES is a nationally representative health survey conducted in the United States, designed and administered by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC). Data collection was reviewed and approved by the National Center for Health Statistics Research Ethics Review Board and signed informed consent forms were obtained from study participants. All data in this study are publicly available at https://www.cdc.gov/nchs/nhanes/index.htm.
Adults (≥20 years old) with the recommended blood pressure were included. The recommended blood pressure was defined as <130 mmHg systolic pressure and <80 mmHg diastolic pressure. 16 Pregnant women were excluded. In addition, participants with DBP below 30 mmHg were considered to have potential measurement error and were excluded. Based on established criteria, we included 25 858 participants from nine NHANES survey cycles, encompassing from 2001 through to 2018 (Figure 1).
FIGURE 1.
The flow chart of study case selection.
2.2. Measurement of exposure variables
Blood pressure values were defined as the average of three or more measurements, measured at 1‐min intervals after a 5‐min quiet rest in the sitting position. After determining the participant's maximum inflation level, three consecutive blood pressure readings will be obtained. A fourth attempt may be made if blood pressure measurements are interrupted or incomplete. All blood pressure measurements (both systolic and diastolic blood pressure) were obtained by NHANES staff using standardized protocols and performed in a mobile examination center.
2.3. Ascertainment of mortality outcomes
We used data from the NHANES public use‐related mortality file from the survey date to 26 April 2022. 17 The National Death Index is a centralized NCHS database of all deaths in the United States. Data on underlying causes of death were used for case definitions according to the International Classification of Diseases, Tenth Revision (ICD‐10). NCHS classifies cardiovascular disease mortality as death from heart disease (ICD‐10 codes I00–I09, I11, I13, and I20‐I51) or cerebrovascular disease (ICD‐10 codes I60–I69), a method validated by the CDC and has been used in CDC reports. 18
2.4. Assessment of covariates
Basic demographic characteristics were obtained through demographic questionnaires, including gender, age, race, education, and marital status. Smoking status were divided into never, former, and current according to the corresponding questionnaire results. We grouped income level according to the poverty to income ratio: low (≤1), middle (1–4), and high (≥4). 19 Body Mass Index was categorized into < 25, 25–30, 30–40, and ≥40 kg/m2. Physical activity was classified into three levels: active physical activity or median physical activity or inactivity, calculated as metabolic equivalents. The prevalence of hypertension is measured by self‐reporting and taking medication for the disease. We determined whether a patient has high blood pressure by answering “Have you ever been told by a doctor or other health professional that you had hypertension also called high blood pressure?” and “Because of your high blood pressure/hypertension, have you ever been told to take prescribed medicine?”. For other diseases such as myocardial infarction, stroke, heart failure, chronic kidney disease, and cancer, we defined them only in the form of self‐reports. Diabetes was defined as fasting plasma glucose ≥126 mg/dL, HbA1c ≥6.5% or a self‐reported doctor's diagnosis of diabetes. 20 We also included uric acid, serum albumin, and high‐density lipoprotein as covariates in the analyses.
2.5. Statistical analysis
Baseline characteristics at different DBP levels (<60 mmHg, 60 to <70 mmHg, 70 to <80 mmHg) were described and differences among the three groups were examined by ANOVA for continuous variables and χ2 test for categorization variables with adjustment for sampling weights.
We divided DBP into dichotomous variables (>60 mmHg and ≤60 mmHg) and used survey‐weighted logistic regression to explore the characteristics of the low DBP population. Survey‐weighted Cox models were used to assess hazard ratios (HRs) and 95% CIs for the association between DBP levels (<60 mmHg, 60 to <70 mmHg, 70 to <80 mmHg) and risk of all‐cause and cardiovascular mortality. The use of hypertension medications may lower the original DBP level of the individuals. This population needs to be distinguished from other people who are not taking anti‐hypertension medications (Figure 2). Therefore, we regrouped the study population as six groups according to DBP and whether they were on medication for hypertension. Survey‐weighted Cox models evaluated associations of the new grouping of DBP (no antihypertensive drugs: <60 mmHg, 60 to <70 mmHg, 70 to <80 mmHg; antihypertensive drugs: <60 mmHg, 60 to <70 mmHg, 70 to <80 mmHg) with survival. Subgroup analyses were also performed in clinically relevant subgroups to validate the final model adding this new grouping variable.
FIGURE 2.
The hypothesized causal relations.
In addition, among total study population, inverse probability of treatment weighting (IPTW) was used to balance the differences in patient characteristics across DBP <50 mmHg (no antihypertensive drugs), DBP <50 mmHg (antihypertensive drugs), DBP 50–60 mmHg (no antihypertensive drugs), DBP 50–60 mmHg (antihypertensive drugs), and DBP 60–80 mmHg to thoroughly compare the prognostication of all‐cause and cardiovascular death and to explore the lower limit of DBP.
For variables with missing values other than the study variables, multiple interpolation method was utilized for deal with them. All statistical analyses were carried out using R software, version 4.1.1.
3. RESULTS
We used data from the 2001–2018 NHANES, which can represent the health status of the civilian resident population of the US. 21 A total of 25 858 participants were included in the study. After weighted, the overall mean age of the participants was 43.17 (16.03) years, including 53.7% women and 68.1% non‐Hispanic white. Among them, 20.5% were self‐reported hypertension patients and 14.8% individuals taking prescription drugs for high blood pressure. Missing data accounted for 0.2%. Participants were divided into three groups according to DBP (<60 mmHg, 60 to <70 mmHg, 70 to <80 mmHg). The baseline characteristics are presented in Table 1.
TABLE 1.
Baseline characteristics of US adults with normal SBP: NHANES 2001–2018.
| DBP, mmHg | |||||||
|---|---|---|---|---|---|---|---|
| No anti‐hypertension drug | Anti‐hypertension drug | ||||||
| <60 | 60 to <70 | 70 to <80 | <60 | 60 to <70 | 70 to <80 | ||
| Characteristics | (N =3877) | (N = 8644) | (N = 8796) | (N = 1210) | (N = 1621) | (N = 1710) | P‐value |
| Age, yrs | 38.02 ± 17.61 | 39.93 ± 14.98 | 41.28 ± 12.84 | 67.23 ± 11.91 | 60.73 ± 12.48 | 56.03 ± 11.20 | <.001 |
| Women, % | 2117 (55.2) | 4893 (58.2) | 4287 (48.8) | 652 (57.4) | 870 (55.4) | 853 (50.7) | <.001 |
| DBP, mmHg | 54.11 (5.04) | 65.12 (2.80) | 74.27 (2.77) | 52.58 (6.08) | 65.02 (2.76) | 74.37 (2.76) | <.001 |
| SBP, mmHg | 108.48 (9.99) | 110.84 (9.19) | 115.38 (7.81) | 113.10 (11.53) | 115.68 (9.51) | 118.48 (7.39) | <.001 |
| Non‐Hispanic White, % | 1632 (63.0) | 3804 (67.5) | 3827 (68.1) | 665 (77.8) | 812 (75.2) | 767 (71.6) | <.001 |
| Marital status, % | |||||||
| Married | 1640 (44.2) | 4305 (52.7) | 4787 (58.0) | 621 (55.5) | 893 (61.2) | 999 (64.0) | <.001 |
| Widowed/divorced/separated | 626 (12.8) | 1283 (13.2) | 1351 (13.7) | 489 (36.3) | 539 (27.3) | 476 (24.1) | |
| Unmarried | 1608 (43.0) | 3050 (34.1) | 2654 (28.4) | 100 (8.2) | 188 (11.5) | 235 (12.0) | |
| Income, a % | |||||||
| ≤1.0 | 863 (18.4) | 1759 (15.6) | 1670 (13.4) | 186 (12.3) | 269 (11.2) | 299 (11.5) | <.001 |
| 1.0–4.0 | 1917 (52.9) | 4067 (48.1) | 4082 (46.1) | 688 (60.0) | 818 (50.0) | 801 (45.5) | |
| ≥4.0 | 740 (28.6) | 2096 (36.3) | 2416 (40.5) | 227 (27.7) | 410 (38.8) | 475 (43.0) | |
| Education, % | |||||||
| No high school graduate | 1035 (18.6) | 2003 (15.1) | 1827 (13.2) | 380 (23.2) | 447 (17.4) | 405 (14.9) | <.001 |
| High school graduate | 891 (23.5) | 1851 (22.0) | 1911 (21.8) | 314 (26.7) | 397 (25.0) | 440 (25.9) | |
| College or above | 1943 (57.9) | 4784 (62.9) | 5052 (65.0) | 513 (50.1) | 775 (57.6) | 864 (59.2) | |
| Smoke, % | |||||||
| Never | 2102 (52.6) | 4987 (56.7) | 5074 (57.5) | 517 (40.7) | 774 (46.0) | 861 (51.7) | <.001 |
| Former | 713 (19.1) | 1625 (19.3) | 1754 (21.3) | 499 (39.7) | 564 (36.9) | 528 (31.8) | |
| Current | 1056 (28.2) | 2028 (24.0) | 1962 (21.2) | 194 (19.6) | 282 (17.0) | 321 (16.5) | |
| BMI, b kg/m2 | |||||||
| <25 | 1638 (46.2) | 3403 (42.2) | 2942 (34.3) | 195 (17.5) | 226 (13.6) | 220 (11.1) | <.001 |
| 25–30 | 1235 (31.7) | 2875 (32.5) | 2986 (34.5) | 403 (33.7) | 519 (31.1) | 543 (32.6) | |
| 30–40 | 831 (18.9) | 1950 (22.0) | 2376 (26.8) | 447 (39.2) | 675 (44.0) | 719 (44.4) | |
| ≥40 | 125(3.2) | 332 (3.3) | 413 (4.4) | 123 (9.6) | 170 (11.4) | 204 (11.9) | |
| Exercise | <.001 | ||||||
| Inactive | 424 (9.4) | 874 (8.7) | 885 (9.0) | 147 (10.4) | 160 (9.1) | 175 (9.7) | |
| Median | 2439 (61.9) | 5611 (65.3) | 5685 (64.6) | 937 (78.0) | 1231 (76.6) | 1232 (70.9) | |
| Active | 1014 (28.7) | 2159 (26.0) | 2226 (26.3) | 126 (11.5) | 230 (14.3) | 303 (19.4) | |
| Uric acid, μmol/L | 302.01 ± 77.34 | 299.14 ± 75.66 | 314.02 ± 78.82 | 363.64 ± 96.97 | 352.45 ± 86.48 | 350.76 ± 86.63 | <.001 |
| Albumin, g/L | 42.82 ± 3.36 | 42.93 ± 3.23 | 43.11 ± 3.18 | 41.29 ± 3.25 | 41.74 ± 3.17 | 42.07 ± 3.15 | <.001 |
| High‐density lipoprotein, mg/dL | 53.98 ± 15.19 | 54.91 ± 15.54 | 53.13 ± 15.88 | 51.23 ± 15.80 | 51.77 ± 16.71 | 50.81 ± 15.63 | <.001 |
| Myocardial infarction, % | 128 (2.9) | 168 (1.5) | 109 (1.0) | 202 (15.5) | 184 (10.3) | 137 (6.9) | <.001 |
| Stroke, % | 83 (1.4) | 106 (1.0) | 108 (0.9) | 161 (11.8) | 142 (7.3) | 132 (6.4) | <.001 |
| Heart failure, % | 93 (1.7) | 86 (0.7) | 56 (0.5) | 172 (13.2) | 169 (9.1) | 100 (3.9) | <.001 |
| Diabetes, % | 339 (5.8) | 684 (5.6) | 660 (5.5) | 546 (40.6) | 609 (33.6) | 525 (27.1) | <.001 |
| Hypertension, % | 238 (5.7) | 510 (5.5) | 736 (8.1) | 1210 (100.0) | 1621 (100.0) | 1710 (100.0) | <.001 |
| Chronic kidney disease, % | 69 (1.5) | 139 (1.3) | 123 (1.3) | 112 (8.0) | 95 (4.4) | 101 (4.8) | <.001 |
| Cancer, % | 270 (6.4) | 524 (6.6) | 479 (6.3) | 253 (22.3) | 313 (21.3) | 251 (16.2) | <.001 |
Values are mean ± SD, median, or n (%).
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure.
Income levels are divided into three groups according to the ratio of poverty to income: low (≤1), medium (1–4), and high (≥4).
Body mass index (BMI) is defined as body weight (kg) divided by height (m) squared.
3.1. Factors associated with low DBP
We used a multiple logistics regression analysis to explore the factors associated with low DBP (<60 mmHg) among the complete study population. Participants aged 70 years or older are significantly more likely to have low DBP when compared with participants younger than 70 years (OR, 4.92; 95% CI, 4.28–5.65). Low DBP were more likely to be observed in women (OR, 1.24; 95% CI, 1.12–1.37). Current smoking was also associated with lower DBP (OR, 1.29; 95% CI, 1.17–1.43). In addition, low DBP was associated with some diseases including myocardial infarction, heart failure and diabetes, but people with high Body Mass Index, high‐density lipoprotein or albumin were less likely to have low DBP. What's more, we found that antihypertensive drugs were also an important and significant correlate of low DBP (OR, 1.52; 95% CI, 1.26–1.83). Full model results are shown in Table S1.
3.2. Relationship between DBP and death
Multivariate survey‐weighted cox models revealed that DBP of less than 60 mmHg were associated with a higher risk of all‐cause death (HR, 1.30; 95% CI, 1.12–1.51) and cardiovascular death (HR, 1.34; 95% CI, 1.00–1.79) compared to those with DBP between 70 and 80 mmHg. This association was not significant among those with hypertension (Table 2).
TABLE 2.
Hazard ratios for all‐cause and cardiovascular mortality according to DBP levels.
| DBP, mmHg | ||||
|---|---|---|---|---|
| Outcome | Population | <60 | 60 to <70 | 70 to <80 |
| All‐cause mortality | Total | 1.30 (1.12–1.51) | 1.02 (0.89–1.18) | 1 [Reference] |
| Hypertensive | 1.19 (0.97–1.45) | 0.99 (0.80–1.22) | 1 [Reference] | |
| Cardiovascular mortality | Total | 1.34 (1.00–1.79) | 1.14 (0.87–1.50) | 1 [Reference] |
| Hypertensive | 1.24 (0.81–1.90) | 1.17 (0.79–1.74) | 1 [Reference] | |
The hazard ratio was estimated based on the survey‐weighted Cox model while adjusting for sociodemographic factors (age, gender, race, education, marital status, income level), lifestyle (smoking status, exercise), diseases (hypertension, diabetes, myocardial infarction, heart failure, stroke, chronic kidney disease, cancer), metabolic indices indexes (Body Mass Index, high‐density lipoprotein, uric acid, albumin), and systolic blood pressure.
We replaced the original grouping of DBP (three groups) with the new grouping of DBP (six groups) in the final model and set DBP 70–80 mmHg (no antihypertensive drugs) as reference group. Only DBP <60 mmHg (no antihypertensive drugs) was associated with a higher risk of all‐cause death (HR, 1.46; 95% CI, 1.21–1.75). DBP <60 mmHg after taking antihypertensive drugs was not associated with a higher risk of all‐cause death (HR, 0.99; 95% CI, 0.73–1.36). In the sensitivity analyses, when we restricted the sample to populations with SBP <120 mmHg, this result was similar. The results of subgroup analysis were presented in Table 3.
TABLE 3.
Hazard ratios (95% CI) for all‐cause mortality by DBP levels stratified by selected covariates in participants with SBP less than 130 mmHg.
| DBP, mmHg | ||||||
|---|---|---|---|---|---|---|
| Variables | No anti‐hypertension drug | Anti‐hypertension drug | ||||
| <60 | 60 to <70 | 70 to <80 | <60 | 60 to <70 | 70 to <80 | |
| Population | ||||||
| All | 1.46 (1.21–1.75) | 1.10 (0.91–1.31) | ref | 0.99 (0.73–1.36) | 0.79 (0.57–1.11) | 0.88 (0.64–1.22) |
| SBP <120 mmHg | 1.39 (1.11–1.73) | 0.90 (0.73–1.10) | ref | 0.79 (0.53–1.18) | 0.61 (0.40–0.94) | 0.74 (0.49–1.14) |
| Age, yrs | ||||||
| <70 | 1.68 (1.35–2.08) | 1.13 (0.88–1.44) | ref | 1.25 (0.84–1.85) | 0.94 (0.62–1.42) | 0.94 (0.61–1.44) |
| ≥70 | 1.46 (1.14–1.86) | 1.03 (0.83–1.28) | ref | 1.04 (0.71–1.52) | 0.88 (0.58–1.33) | 0.88 (0.58–1.34) |
| Smoking | ||||||
| Current | 1.29 (0.94–1.78) | 1.17 (0.88–1.56) | ref | 0.86 (0.49–1.51) | 0.60 (0.33–1.08) | 0.93 (0.55–1.55) |
| Others | 1.29 (0.78–2.13) | 0.97 (0.55–1.72) | ref | 1.52 (0.76–3.05) | 1.64 (0.79–3.43) | 1.91 (0.90–4.03) |
| Myocardial infarction | ||||||
| Yes | 1.49 (1.23–1.79) | 1.11 (0.91–1.35) | ref | 0.99 (0.71–1.38) | 0.76 (0.53–1.10) | 0.84 (0.60–1.19) |
| No | 1.04 (0.59–1.84) | 0.82 (0.45–1.50) | ref | 0.70 (0.30–1.63) | 0.30 (0.13–0.68) | 0.77 (0.34–1.74) |
| Stroke | ||||||
| Yes | 1.48 (1.22–1.79) | 1.12 (0.93–1.34) | ref | 1.00 (0.71–1.40) | 0.94 (0.67–1.33) | 0.87 (0.62–1.23) |
| No | 1.04 (0.59–1.84) | 0.88 (0.46–1.69) | ref | 0.98 (0.47–2.02) | 1.00 (0.50–1.99) | 0.90 (0.42–1.97) |
| Heart failure | ||||||
| Yes | 1.47 (1.21–1.77) | 1.11 (0.92–1.35) | ref | 1.06 (0.76–1.46) | 0.85 (0.60–1.20) | 0.91 (0.64–1.29) |
| No | 1.81 (0.71–4.64) | 0.69 (0.34–1.39) | ref | 0.99 (0.38–2.59) | 1.09 (0.41–2.93) | 1.59 (0.63–4.00) |
| Chronic kidney disease | ||||||
| Yes | 1.44 (1.20–1.73) | 1.11 (0.92–1.33) | ref | 0.98 (0.71–1.37) | 0.78 (0.55–1.10) | 0.85 (0.62–1.18) |
| No | 1.73 (1.19–2.52) | 1.09 (0.69–1.73) | ref | 0.88 (0.52–1.50) | 0.73 (0.42–1.25) | 0.72 (0.40–1.30) |
| Diabetes | ||||||
| Yes | 1.38 (1.12–1.70) | 1.09 (0.90–1.32) | ref | 1.06 (0.76–1.49) | 0.80 (0.55–1.18) | 0.90 (0.64–1.27) |
| No | 1.67 (1.07–2.61) | 1.16 (0.80–1.68) | ref | 1.28 (0.73–2.23) | 0.99 (0.51–1.92) | 1.21 (0.67–2.19) |
| Cancer | ||||||
| Yes | 1.44 (1.17–1.76) | 1.10 (0.89–1.35) | ref | 0.93 (0.64–1.35) | 0.74 (0.51–1.06) | 0.76 (0.54–1.06) |
| No | 1.39 (1.11–1.73) | 0.90 (0.73–1.10) | ref | 0.79 (0.53–1.18) | 0.61 (0.40–0.94) | 0.74 (0.49–1.14) |
Abbreviation: DBP, diastolic blood pressure.
To validate these results and explore the lower limit of DBP, IPTW was used to select matching subjects among the individuals with DBP ≥60 mmHg. Compared with patients with DBP ≥60 mmHg, those with DBP <50 mmHg (no antihypertensive drugs) or DBP 50–60 mmHg (no antihypertensive drugs) had a significantly increased risk of all‐cause or cardiovascular mortality (Figure 3). DBP 50–60 mmHg (antihypertensive drugs) was not associated with a higher risk of all‐cause or cardiovascular mortality. DBP <50 mmHg (antihypertensive drugs) was only associated with a higher risk of all‐cause mortality.
FIGURE 3.
Hazard ratios of all‐cause and cardiovascular mortality with 95% confidence intervals adjusting for IPTW.
4. DISCUSSION
In a US population with normal blood pressure (<130/80 mmHg), we examined the factors associated with low DBP (<60 mmHg) and found antihypertensive drug is an important factor that contributes to DBP below 60 mmHg. But the pre‐existing risk does not increase further with an additional reduce of DBP after antihypertensive drug treatment.
Associations between DBP and cardiovascular events as well as death had been observed in many previous studies. 22 , 23 This relationship was described by a j‐shape phenomenon, 24 which could be explained by lower DBP leading to lower coronary perfusion and myocardial injury. 11 , 25 , 26 Those viewpoints require us to consider the lower bound of DBP when reinforcing SBP reduction. A recent post hoc analysis of the SPRINT trial and the Action to Control Cardiovascular Risk in Diabetes–Blood Pressure trial also demonstrated that diastolic hypotension was associated with adverse cardiovascular outcomes. 27 Moreover, other studies had raised concerns about the poor prognosis related to DBP reduction due to intensive SBP reduction, 10 , 13 , 28 and the same predicament occurred in isolated systolic hypertension patients with low DBP (<70 mmHg). Nearly half of this population did not receive effective hypertension treatment. 29 , 30 We also got the same results in our study, but actually, whether this correlation indicates a causal relationship between the reduced DBP and the increased risk of death is unclear.
In our study, we found that numerous factors are associated with low DBP, including heart failure, myocardial infarction, diabetes and advanced age. The decrease in DBP in diabetic patients is more likely to attributable to the proinflammatory effects of glucose on vascular injury and remodeling. 31 , 32 The decline in DBP also may be attributed to pressure‐induced damage to the blood vessel wall in hypertensive patients, resulting in arterial stiffness. 33 These diseases usually present with increased blood pressure early on but eventually lead to a decrease in DBP as the disease progresses. What's more, DBP inevitably decreases with age due to age‐related aortic stiffness and less blood remaining in the aorta when the ventricle begins to relax. 34 And there have also been studies that suggest that frailty may manifest as low DBP in the elderly population. 35 , 36 , 37 , 38 , 39 Therefore, we speculated that low DBP is probably a sign of advanced age and worse physical condition. The association between low DBP and death may be established through those factors.
Of these causes, we consider the use of antihypertensive drug as a special factor. First, we can infer definitive causal link between reduced DBP and the use of antihypertensive drugs. The use of antihypertensive drugs may result in a reduction of original DBP level. Secondly, the reduce of DBP resulting from the intervention of antihypertensive drugs does not mean a deterioration in physical condition. Therefore, in the final model, we regrouped the study population as six groups according to DBP and whether they were on medication for hypertension. We found that only DBP <60 mmHg (no antihypertensive drugs) was associated with a higher risk of all‐cause death, whereas DBP <60 mmHg after taking antihypertensive drugs was not. Therefore, we may infer that original DBP level was more closely linked to the all‐cause death. But this relationship is not the cause‐effect relationship. The DBP for both groups was below 60 mmHg, but there were considerable differences in the correlation to death. Worse vascular condition and poor physical condition might very well probably serve as a bridge to bring DBP and the risk of death together. The reduce of DBP caused by the extrinsic intervention will not increase the pre‐existing risk.
We also analyzed the extreme cases of DBP by using IPTW. DBP <50 mmHg after taking antihypertensive drugs was associated with a higher risk of all‐cause death. Even after intensive blood pressure lowering, DBP is rarely reduced by more than 10 mmHg. 40 We think that this population may have the low level of DBP before taking the medication and be at high risk of the death. In fact, we do associate low DBP with poor outcomes, but it does not appear to be an independent risk factor. If the harm of low DBP may not be self‐inflicted, it may be too conservative to assume that DBP is the cause, so that people with lower DBP may not benefit from intensive blood pressure control. One study showed that the effect of enhanced blood pressure control did not vary with baseline DBP. 39 A Mendelian randomized study confirmed this causal relationship, showing that low DBP did not increase or even decrease the risk of myocardial infarction.
Therefore, low DBP should not be a barrier to intensive blood pressure reduction, and we should pay more attention to other conditions that may be reflected in low DBP. The reasons for low DBP in these patients are worth exploring, and controlling these disorders appears to be more beneficial than actually controlling DBP.
5. CONCLUSION
Advanced age and some diseases are strongly associated with low DBP in US population with normal blood pressure (<130/80 mmHg). The association between low DBP and death may be established through those factors. The pre‐existing risk does not increase further with an additional reduce of DBP after antihypertensive drugs treatment.
AUTHOR CONTRIBUTIONS
Concept and design: Wang, Ju. Acquisition, analysis, or interpretation of data: Wang, Yu. Drafting of the manuscript: Wang, Cao. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Wang, Yu.
Supporting information
Supplementary Information
ACKNOWLEDGMENTS
Throughout the writing of this dissertation, I have received a great deal of support and assistance. I would like to thank my supervisor, Weizhu Ju, whose expertise was invaluable in formulating the research questions and methodology. And I could not have completed this dissertation without the support of my girlfriend, who provided stimulating discussions as well as happy distractions to rest my mind outside of my research.
Wang Z, Yu C, Cao X, He Y, Ju W. Association of low diastolic blood pressure with all‐cause death among US adults with normal systolic blood pressure. J Clin Hypertens. 2023;25:326–334. 10.1111/jch.14646
Zhe Wang and Chuanchuan Yu contributed equally to this work.
DATA AVAILABILITY STATEMENT
Our data are obtained from the publicly available database NHANES. All data are publicly available at https://www.cdc.gov/nchs/nhanes/index.htm.
REFERENCES
- 1. Zhou B, Carrillo‐Larco RM, Danaei G, et al. Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population‐representative studies with 104 million participants. Lancet. 2021;398:957‐980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Banegas JR, Ruilope LM, de la Sierra A, et al. Relationship between clinic and ambulatory blood‐pressure measurements and mortality. N Engl J Med. 2018;378:1509‐1520. [DOI] [PubMed] [Google Scholar]
- 3. Kim CS, Choi HS, Bae EH, et al. Optimal blood pressure target and measurement in patients with chronic kidney disease. Korean J Intern Med. 2019;34:1181‐1187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Guerrot D, Humalda JK. Blood pressure targets in chronic kidney disease: an update on the evidence. Curr Opin Nephrol Hypertens. 2020;29:327‐332. [DOI] [PubMed] [Google Scholar]
- 5. Flint AC, Conell C, Ren X, et al. Effect of systolic and diastolic blood pressure on cardiovascular outcomes. N Engl J Med. 2019;381:243‐251. [DOI] [PubMed] [Google Scholar]
- 6. Kannel WB, Dawber TR, McGee DL. Perspectives on systolic hypertension. The Framingham study. Circulation. 1980;61:1179‐1182. [DOI] [PubMed] [Google Scholar]
- 7. SPRINT Research Group ; Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood‐pressure control. N Engl J Med. 2015;373:2103‐2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Zhang W, Zhang S, Deng Y, et al. Trial of intensive blood‐pressure control in older patients with hypertension. N Engl J Med. 2021;385:1268‐1279. [DOI] [PubMed] [Google Scholar]
- 9. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Pr , 2018.
- 10. Böhm M, Schumacher H, Teo KK, et al. Achieved diastolic blood pressure and pulse pressure at target systolic blood pressure (120‐140mmHg) and cardiovascular outcomes in high‐risk patients: results from ONTARGET and TRANSCEND trials. Eur Heart J. 2018;39:3105‐3114. [DOI] [PubMed] [Google Scholar]
- 11. McEvoy JW, Chen Y, Rawlings A, et al. Diastolic blood pressure, subclinical myocardial damage, and cardiac events: implications for blood pressure control. J Am Coll Cardiol. 2016;68:1713‐1722. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Brouwer TF, Vehmeijer JT, Kalkman DN, et al. Intensive blood pressure lowering in patients with and patients without type 2 diabetes: a pooled analysis from two randomized trials. Diabetes Care. 2018;41:1142‐1148. [DOI] [PubMed] [Google Scholar]
- 13. Lee TC, Cavalcanti RB, McDonald EG, et al. Diastolic hypotension may attenuate benefits from intensive systolic targets: secondary analysis of a randomized controlled trial. Am J Med. 2018;131:1228‐1233. [DOI] [PubMed] [Google Scholar]
- 14. Koracevic G, Stojanovic M, Kostic T, et al. Unsolved problem: (isolated) systolic hypertension with diastolic blood pressure below the safety margin. Med Princ Pract. 2020;29:301‐309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Arvanitis M, Qi G, Bhatt DL, et al. Linear and nonlinear mendelian randomization analyses of the association between diastolic blood pressure and cardiovascular events: the J‐curve revisited. Circulation. 2021:895‐906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Pr. J Am Coll Cardiol. 2018;71:e127‐e248. [DOI] [PubMed] [Google Scholar]
- 17. National Center for Health Statistics . Office of Analysis and Epidemiology. The Linkage of National Center for Health Statistics Survey Data to the National Death Index – 2015 Linked Mortality File (LMF): Methodology Overview and Analytic Considerations. 2018:1‐25.
- 18. WHO . Međunarodna klasifikacija bolesti i srodnih zdravstvenih problema. Hrvatski zavod za javno zdravstvo. 2012:267‐334. [Google Scholar]
- 19. Odutayo A, Gill P, Shepherd S, et al. Income disparities in absolute cardiovascular risk and cardiovascular risk factors in the United States, 1999–2014. JAMA Cardiol. 2017;2:782‐790. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. American Diabetes Association . 2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2019. Diabetes Care. 2019;42:S13‐S28. [DOI] [PubMed] [Google Scholar]
- 21. Zipf G, Chiappa M, Porter KS, et al. National health and nutrition examination survey: plan and operations, 1999–2010. Vital Health Stat 1: Programs and Collection Procedures. 2013:1999‐2010. [PubMed] [Google Scholar]
- 22. Protogerou AD, Safar ME, Iaria P, et al. Diastolic blood pressure and mortality in the elderly with cardiovascular disease. Hypertension. 2007;50:172‐180. [DOI] [PubMed] [Google Scholar]
- 23. Tsujimoto T, Kajio H. Low diastolic blood pressure and adverse outcomes in heart failure with preserved ejection fraction. Int J Cardiol. 2018;263:69‐74. [DOI] [PubMed] [Google Scholar]
- 24. Farnett L, Mulrow CD, Linn WD, et al. The J‐curve phenomenon and the treatment of hypertension: is there a point beyond which pressure reduction is dangerous? JAMA. 1991;265:489‐495. [PubMed] [Google Scholar]
- 25. Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006;144:884‐893. [DOI] [PubMed] [Google Scholar]
- 26. Bhatt DL. Troponin and the J‐curve of diastolic blood pressure: when lower is not better. J Am Coll Cardiol. 2016;68:1723‐1726. [DOI] [PubMed] [Google Scholar]
- 27. Li J, Somers VK, Gao X, et al. Evaluation of optimal diastolic blood pressure range among adults with treated systolic blood pressure less than 130 mm Hg. JAMA Netw Open. 2021;4:1‐13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Khan NA, Rabkin SW, Zhao Y, et al. Effect of lowering diastolic pressure in patients with and without cardiovascular disease: analysis of the SPRINT (systolic blood pressure intervention trial). Hypertension. 2018;71:840‐847. [DOI] [PubMed] [Google Scholar]
- 29. Franklin SS, Chow VH, Mori AD, et al. The significance of low DBP in US adults with isolated systolic hypertension. J Hypertens. 2011;29:1101‐1108. [DOI] [PubMed] [Google Scholar]
- 30. Wang S, Li J, Yan G, et al. Assessment of isolated systolic hypertension with lower diastolic and the risk of cardiovascular disease in older adults. Int J Cardiol. 2017;242:20. [DOI] [PubMed] [Google Scholar]
- 31. Hamilton SJ, Watts GF. Endothelial dysfunction in diabetes: Pathogenesis, significance, and treatment. Rev Diabet Studies. 2013;10:133‐156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Assar M El, Angulo J, Rodríguez‐Mañas L. Diabetes and ageing‐induced vascular inflammation. J Physiol. 2016; 594:2125‐2146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Delgado J, Bowman K, Ble A, et al. Blood pressure trajectories in the 20 years before death. JAMA Intern Med. 2018;178:93‐99. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Franklin SS, Gustin IV W, Wong ND, et al. Hemodynamic patterns of age‐related changes in blood pressure: the Framingham heart study. Circulation. 1997;96:308‐315. [DOI] [PubMed] [Google Scholar]
- 35. Basile G, Catalano A, Mandraffino G, et al. Relationship between blood pressure and frailty in older hypertensive outpatients. Aging Clin Exp Res. 2017;29:1049‐1053. [DOI] [PubMed] [Google Scholar]
- 36. Sze S, Pellicori P, Zhang J, et al. Identification of frailty in chronic heart failure. JACC Heart Fail. 2019;7:291‐302. [DOI] [PubMed] [Google Scholar]
- 37. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:146‐157. [DOI] [PubMed] [Google Scholar]
- 38. Benetos A, Petrovic M, Strandberg T. Hypertension management in older and frail older patients. Circ Res. 2019;124:1045‐1460. [DOI] [PubMed] [Google Scholar]
- 39. Beddhu S, Chertow GM, Cheung AK, et al. Influence of baseline diastolic blood pressure on effects of intensive compared with standard blood pressure control. Circulation. 2018;137:134‐143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016;315:2673. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Information
Data Availability Statement
Our data are obtained from the publicly available database NHANES. All data are publicly available at https://www.cdc.gov/nchs/nhanes/index.htm.